Significance of Signal Transduction Mechanisms in the Effects of Drugs. Tachyphylaxis and Tolerance to Drugs

Question 1

Signal Transduction

Pharmacological Significance

Answer 1

Allow variation of effects of certain drugs
Multiplies and amplifies effect
Triggers a cascade

Personalised Medicine; Disease Drug Interaction
Specific drug for specific patient for his disease
Which drugs most appropriate or CI

Question 2

Main Types of Receptors

Answer 2

Ligand Gated Ion Channel
G Protein Coupled Receptor
Kinase Linked Receptors
Nuclear Receptors

Question 3

Receptors

Answer 3

Specific glycoprotein
No other known function other than letting cell know about ligand binding

No function without agonist binding

Question 4

Basic Mechanism of Drug Action on
   Receptors
   Ion Channels
   Enzymes
   Transporters

Answer 4

Receptors
Agonist, Antagonist

Ion Channel
Blockers, Modulators

Enzymes
Inhibitor, False substrate, Pro-drug

Transporters
Normal, Inhibitor, False Substrate

Question 5

Ionotropic Receptors (Ligand Gated Ion Channels)

Structure
Examples

Answer 5

4-5 subunits
1 subunit consists of 4 transmembrane alpha helices
Ligand binding subunit in EC space

Very fast: milliseconds

Examples
ACh N R
GABA A R
5HT3 R

Direct channel opening-> hyperpolarisation or depolarisation-> cellular effects

Question 6

G Protein Coupled Receptors

Answer 6

Metabotropic

1 polypeptide chain; 7 transmembrane alpha helices
EC ligand binding subunit
IC effector subunit

Signal transduction takes seconds to minutes

Examples
   Muscarinic ACh R
      M1: Gq (neuronal)
      M2: Gi
      M3: Gq (glandular)

Question 7

G Protein Coupled Receptor

Effector: Adenylate Cyclase

Answer 7

Mediated Effects
   SM Relaxation
   Cardiac muscle contraction
   Increased neuronal excitability
   Increase of gastric acid secretion

Gs: Adrenergic Beta Receptors (1 and 2)
Dopamine D1 Receptor (dilation of renal vessels)
Histamine H2 Receptor (secretion of gastric acid)

Gi: ACh M2
Adrenergic alpha 2 Receptor (decrease further NA
release)
Dopamine D2 Receptor

Question 8

G Protein Coupled Receptor

Effector: Phospholipase C

Answer 8

Mediated Effects
   SM Contraction
   Cardiac Muscle Contraction
   NT Release
   Hormone Secretion

Gq: ACh M1 and M3
Adrenergic alpha 1 Receptors-> vasoconstriction
Histamine H1 Receptor-> allergic reactions
Vasopressin, Angiotensin II

Question 9

G Protein Coupled Receptor

Gq Signal Transduction Pathways

Answer 9

Activation of Phospholipase C-> IP3 and DAG release
from PIP2
IP3-> Ca from SR (this with DAG activates PK-C)
DAG-> activation PK-C-> phosphorylation of tissue
specific substrate enzymes

In SM: release of Ca from SR-> Ca-CM-> MLCK->
contraction

Question 10

G Protein Coupled Receptor

Gs Signal Transduction Pathway

Answer 10

Adenylate cyclase: ATP-> cAMP

cAMP-> PK-A activation

PK-A phosphorylates a set of tissue specific substrate enzymes
Ex: Lipase, Glucose 1 Phosphatase

PK-A also phosphorylates transcription factors (ex CREB)

SM
Increase cAMP-> inhibition of MLCK-> relaxation

Cardiac Muscle
Increase cAMP-> Increase PK-A-> activation of Ca channel-> further release Ca from SR-> Contraction

Question 11

G Protein Coupled Receptor

Effector: Phospholipase A2

Answer 11

From phospholipids of all cell membrane arachidonic acid
From that various eicosanoids are formed

Eicosanoids may act as 1st messengers (local hormones; autacoids)
or as second messengers inside cytoplasm

Question 12

Endothelium Dep. Vasodilation

Answer 12

Endothelial Cell:
Ca activates NOS
NOS: L Arginine-> NO

NO then passes to SM
Activates G Cyclase: GTP-> cGMP-> G Kinase-> Relaxation

Question 13

G Protein Coupled Receptor

Effector Ion Channels

Answer 13

Capable of directly influencing functions of K, Ca, and Na channels without usage of 2nd messengers

Example
M2 Muscarinic Agonist: Increases K permeability

Question 14

Enzyme (Kinase) Linked Receptor

Answer 14

EC ligand binding and IC catalytic subunit

Signal transduction takes minutes to hours

Tyrosine Kinase Linked (Imatinib)
Guanylate Cyclase Linked (ANP) (increase cGMP)
Tyrosine Phosphatase Linked
Serine/Threonine Kinase Linked

Examples
GF
Insulin
Cytokines

GF Type
Autophosphoylation-> dimerisation-> Ras/Raf/Map (–> large signal amplification)

Cytokine R Type
JAK/STAT–> nucleus

Question 15

Intracellular Receptors

Answer 15

Ligand binding subunit (C Terminal)
DNA binding subunit (central part)
Transcription activating subunit (N terminal)

Signal Transduction takes hours-> days

Agonist binding-> change of conformation-> dimerisation-> nucleus-> binding to HRE-> increased gene activation or gene repression transcription

Examples
   Steroid Hormones
   Thyroid Hormones
   Vit D
   Retinoids

Question 16

Tachyphylaxis and Tolerance

Answer 16

Tachyphylaxis
Decreased drug action post continuous drug admin
within minutes or hours

Tolerance
Decreased drug action which develops slowly and
gradually within days/weeks

–> same dose evokes smaller effect; higher dose req. for same effect

Refractory: complete loss of absence of th effect. May be due to genetic variations: ex aspirin

Extent can differ for different drug actions
Opioids: marked tolerance for analgesic, not for ex
constipation, myosis

Can be basis for th application of drug
Ex: GnRH analogues

Mechanism can either be pharmacokinetic- or dynamic

Question 17

Tachyphylaxis and Tolerance

Mechanisms

Answer 17

Changes in ligand binding or R activation (R desensiti.)
fast and marked
P of IC sites of R protein-> decreased potential to
induce signal transduction process

Decreased/ Increased # of Receptors (down/up regula.)
Slower process
Ex: Hormone R decrease when agonist admin
b2 R decrease when agonist conc is low

Depletion of Mediators: usually -> Tachyphylaxis
Ex: amphetamine depletes monoamine stores
nitrates deplete SH groups

Increased Degradation : Enzyme induction

Physiological Adaption–> Tolerance
Homeostatic counter reg act against drugs
Thiazine diuretics-> compensat. RAAS activation

Active Pumping Out
MDR

AB production against drug if drug behaves as ag
Ex: Insulin